Inflammatory bowel diseases (IBD), such as Crohn's disease and ulcerative colitis, are intractable diseases repeating the regression and exacerbation of their pathological states. The cause of these diseases has not yet become clear although autoimmune disorders, enterobacilli, etc., are presumed to be involved (Fiocchi C. Inflammatory bowel disease: etiology and pathogenesis. Gastroenterology 1998; 115: 182-205). Currently, various medications are given to treat IBD; however, some patients cannot continue therapy because conventional treatments fail to regress their pathological conditions or because of the side effects of the medications. For those cases in which medications cannot rectify pathological conditions, surgery to remove the gastrointestinal tract is unavoidable. Therefore, in view of QOL (Quality of Life), the development of medications that are effective and pose little side effects is in demand.
It is known that oxidative stress caused by reactive oxygen species is involved in various inflammatory reactions including colitis. Redox regulation, a series of mechanisms regulating intracellular signaling, produces or eliminates reactive oxygen species to control intracellular signaling. Thioredoxin (TRX) is one of the principal factors responsible for this redox regulation. TRX is a multifunctional molecule that has been cloned as an adult T cell leukemia-derived factor and has the ability to control redox reactions by the thiol-disulfide reaction of the Cys-Gly-Pro-Cys sequence (SEQ ID NO:1) (Tagaya Y, Maeda Y, Mitsui A, Kondo N, Matsui H, Hamuro J, Brown N, Arai K, Yokota T, Wakasugi H, ATL-derived factor (ADF), an IL-2 receptor/Tac inducer homologous to thioredoxin; possible involvement of dithiol-reduction in the IL-2 receptor induction. Embo J 1989; 8: 757-64). Various reports disclose functions of TRX, such as the inhibition of apoptosis and enhancement of cytophylaxis reaction by diminishing the reduction or production of reactive oxygen species (ROS), activating transcription factors such as NF-kB, Refi, etc., inhibiting signal transduction to MAPK by ASK-1 inactivation (Powis G, Montfort WR. Properties and biological activities of thioredoxins. Annu Rev Biophys Biomol Struct 2001; 30: 421-55). Accordingly, TRX is known to be involved in enhancing biophylaxis.
In IBD-affected mucosal tissues, although the production of ROS is increased, the production of antioxidative molecules, such as Cu/Zn-SOD, reduced thiols, and the like, is decreased (Lih-Brody L, Powell S R, Collier K P, Reddy G M, Cerchia R, Kahn E, Weissman G S, Katz S, Floyd R A, McKinley MJ, Fisher S E, Mullin G E. Increased oxidative stress and decreased antioxidant defenses in mucosa of inflammatory bowel disease. Dig Dis Sci 1996; 41: 2078-86; McKenzie S J, Baker M S, Buffinton G D, Doe W F. Evidence of oxidant-induced injury to epithelial cells during inflammatory bowel disease. J Clin Invest 1996; 98: 136-41). Therefore, it is said that IBD-affected lesions face an imbalance in the production of ROS and antioxidative molecules.
Likewise, in the lesions of dextran sulfate sodium (DSS)-induced inflammatory bowel diseases, which are IBD models, a decrease in the production of antioxidative molecules is reported (Korenaga D, Takesue F, Kido K, Yasuda M, Inutsuka S, Honda M, Nagahama S. Impaired antioxidant defense system of colonic tissue and cancer development in dextran sulfate sodium-induced colitis in mice. J Surg Res 2002; 102: 144-9). These DSS-induced colitis model are likely to exhibit the pathological conditions of relatively reproducible colitis (Okayasu I, Hatakeyama S, Yamada M, Ohkusa T, Inagaki Y, Nakaya R. A novel method in the induction of reliable experimental acute and chronic ulcerative colitis in mice. Gastroenterology 1990; 98: 694-702), and are widely used in evaluating therapeutic effects of medical agents.
The inventors found that thioredoxin produces colitis-inhibiting effects using DSS-induced colitis model mice, and have accomplished the present invention based on this finding.
An object of the invention is to provide a prophylactic and therapeutic agent for an inflammatory bowel disease comprising thioredoxin as an active ingredient, and a method for treating an inflammatory bowel disease using such an agent.